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WO2008006096A1 - Synthèse de métaxalone - Google Patents

Synthèse de métaxalone Download PDF

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Publication number
WO2008006096A1
WO2008006096A1 PCT/US2007/073015 US2007073015W WO2008006096A1 WO 2008006096 A1 WO2008006096 A1 WO 2008006096A1 US 2007073015 W US2007073015 W US 2007073015W WO 2008006096 A1 WO2008006096 A1 WO 2008006096A1
Authority
WO
WIPO (PCT)
Prior art keywords
metaxalone
process according
dimethylphenoxy
propanol
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2007/073015
Other languages
English (en)
Inventor
Iulia Demian
Alice Digiulian Mcclure
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim Chemicals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim Chemicals Inc filed Critical Boehringer Ingelheim Chemicals Inc
Publication of WO2008006096A1 publication Critical patent/WO2008006096A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms

Definitions

  • the present invention relates to an efficient synthesis of metaxalone.
  • Metaxalone or 5-[(3,5-dimethylphenoxy)methyl]-2-oxazolidinone is a skeletal muscle relaxant having the following chemical structure:
  • Metaxalone is a central nervous system depressant that has sedative and skeletal muscle relaxant effects and is indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomforts associated with acute, painful musculoskeletal conditions.
  • the invention is directed to a more efficient and economic synthesis route for metaxalone consisting of a single reaction step.
  • the process involves reacting 3-(3,5- dimethylphenoxy)-l-amino-2-propanol with methyl carbamate in the presence of a strong base such as LiNH 2 , sodium methylate, KOH, or NaOH to obtain metaxalone.
  • a strong base such as LiNH 2 , sodium methylate, KOH, or NaOH.
  • the crude metaxalone is then isolated and purified by crystallization from butyl acetate.
  • the overall yield for this process is approximately 65%-68% pure metaxalone.
  • the process is illustrated in Scheme 1 below.
  • the term "about” or “approximately” means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.
  • the yield of each of the reactions described herein is expressed as a percentage of the theoretical yield.
  • reaction conditions and reaction times may vary depending on the particular reagents used. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in this Experimental Examples section. Typically, reaction progress may be monitored by high performance liquid chromatography (HPLC) or thin layer chromatography (TLC), if desired, and intermediates and products may be purified by chromatography on silica gel and/or by recrystallization.
  • HPLC high performance liquid chromatography
  • TLC thin layer chromatography
  • reaction time is solely a function of temperature
  • amount of 3-(3,5-dimethylphenoxy)-l-amino-2-propanol residual (unreacted) starting material is also a function of temperature
  • concentration of the impurities is a function of both temperature and methyl carbamate stoichiometry, where lower temperatures and lower mole ratios of methyl carbamate to 3-(3,5-dimethylphenoxy)-l-amino-2-propanol minimize the impurities formation
  • d the concentration of the impurities is a function of both temperature and methyl carbamate stoichiometry, where lower temperatures and lower mole ratios of methyl carbamate to 3-(3,5-dimethylphenoxy)-l-amino-2-propanol minimize the impurities formation
  • the yield is increased at lower mole ratios of methyl carbamate to 3 -(3, 5- dimethylphenoxy)-l-amino-2-propanol and at higher temperatures.
  • the reaction should be run at the lower temperature in order to minimize the formation of impurities and lower molar ratio of methyl carbamate to 3 -(3, 5- dimethylphenoxy)-l-amino-2-propanol is preferable.
  • methyl carbamate stoichiometry is determinant for the formation of the major impurity.
  • the limit of diminishing returns has been demonstrated to be at 1.25-1.35 equivalents of methyl carbamate.
  • Table 1 the data also show that LiNH 2 or CH 3 ONa can be used interchangeably.
  • the 3-(3,5-dimethylphenoxy)-l-amino-2-propanol starting material has to be of good quality including chemical purity and color. Colored impurities are only partially removed by the butyl acetate treatment and impact the quality of the final product with respect to color. Accordingly, it is advantageous for carbon treatment to be applied either to the crude or to the final purification step.
  • the filtrate from the final purification can be recycled in part. Unreacted 3-(3,5- dimethylphenoxy)-l-amino-2-propanol can be separated from the concentrated filtrates and can be recycled after separation by filtration and drying. A better alternative would be to run the reaction as close to completion as practical.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

L'invention concerne un procédé de préparation de métaxalone, ledit procédé comprenant la réaction de 3-(3,5-diméthylphénoxy)-1-amino-2-propanol avec du carbamate de méthyle en présence d'une base forte pour obtenir la métaxalone.
PCT/US2007/073015 2006-07-07 2007-07-09 Synthèse de métaxalone Ceased WO2008006096A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US81907306P 2006-07-07 2006-07-07
US60/819,073 2006-07-07

Publications (1)

Publication Number Publication Date
WO2008006096A1 true WO2008006096A1 (fr) 2008-01-10

Family

ID=38663258

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2007/073015 Ceased WO2008006096A1 (fr) 2006-07-07 2007-07-09 Synthèse de métaxalone

Country Status (1)

Country Link
WO (1) WO2008006096A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012104139A1 (fr) * 2011-02-01 2012-08-09 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Procédé de préparation de métaxalone

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3062827A (en) * 1959-06-19 1962-11-06 Robins Co Inc A H 5-(3', 5'-dialkylphenoxymethyl)-2-oxazolidones
US3299088A (en) * 1959-06-19 1967-01-17 Robins Co Inc A H Halo-substituted phenoxymethyl oxazolidones
US6538142B1 (en) * 2002-04-18 2003-03-25 Farchemia S.R.L. Process for the preparation of metaxalone
WO2003061552A2 (fr) * 2002-01-14 2003-07-31 Sun Pharmaceutical Industries Limited Procede relatif a l'elaboration de 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone sensiblement pure

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3062827A (en) * 1959-06-19 1962-11-06 Robins Co Inc A H 5-(3', 5'-dialkylphenoxymethyl)-2-oxazolidones
US3299088A (en) * 1959-06-19 1967-01-17 Robins Co Inc A H Halo-substituted phenoxymethyl oxazolidones
WO2003061552A2 (fr) * 2002-01-14 2003-07-31 Sun Pharmaceutical Industries Limited Procede relatif a l'elaboration de 5-(3,5-dimethylphenoxy)methyl-2-oxazolidinone sensiblement pure
US6538142B1 (en) * 2002-04-18 2003-03-25 Farchemia S.R.L. Process for the preparation of metaxalone

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012104139A1 (fr) * 2011-02-01 2012-08-09 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Procédé de préparation de métaxalone
CN103298797A (zh) * 2011-02-01 2013-09-11 方济各安吉利克化学联合股份有限公司 美他沙酮的制备方法
CN103298797B (zh) * 2011-02-01 2016-04-20 方济各安吉利克化学联合股份有限公司 美他沙酮的制备方法
US9416116B2 (en) 2011-02-01 2016-08-16 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Method of preparation of metaxalone
AU2012213666B2 (en) * 2011-02-01 2016-09-08 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Method of preparation of metaxalone
EA024417B1 (ru) * 2011-02-01 2016-09-30 Ацьенде Кимике Рьюните Анджелини Франческо А.К.Р.А.Ф. С.П.А. Способ получения метаксалона
KR101907599B1 (ko) 2011-02-01 2018-10-12 아지엔드 키미쉐 리유나이트 안젤리니 프란체스코 에이.씨.알.에이.에프. 에스.피.에이 메탁살론의 제조 방법

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